Environmental and Molecular Mutagenesis

CARLo‐5 as an oncogenic gene in endometrial carcinoma

The long noncoding RNA CARLo‐5 is dysregulated in multiple types of human cancers. High CARLo‐5 is a promising predictive factor for various cancers, including endometrial carcinoma (EC). Our previous study showed that the expression level of CARLo‐5 was associated with advanced FIGO stage (The International Federation of Gynecology and Obstetrics), lymph node metastasis, and the poor survival of patients with EC. In the present study, we demonstrated that the downregulation of CARLo‐5 could affect the proliferation, cell cycle, migration, and invasion of EC cell lines HEC‐1B and KLE cells. The oncogenic activity of CARLo‐5 was also confirmed with in vivo data. Mechanistically, CARLo‐5 could affect the expression of CDK/CDKN1A and MMP2/9, which have been reported to be regulated by CARLo‐5 and associated with cell cycle and motility. In conclusion, this study is the first to discover the biological function and mechanism of CARLo‐5 in regulating the biological characteristics of EC cells. Targeting CARLo‐5 and its pathway might provide new biomarkers or potential therapies target for patients with EC. Environ. Mol. Mutagen. 61:256–265, 2020. © 2019 Wiley Periodicals, Inc.

Decoding the Impact of Genetic Polymorphisms in Xenobiotic Metabolizing Enzymes and Ovarian Cancer: A Comprehensive Review

ABSTRACT Ovarian cancer (OC), the third most common and fatal gynecological malignancy, is a heterogeneous disease characterized by genomic instability. The interaction between genetic and environmental factors, including xenobiotics, plays a crucial role in OC initiation, progression, and treatment resistance. Xenobiotic metabolism (XM) is a key process for metabolizing and detoxifying environmental carcinogens, drugs, and other xenobiotics. Variations in XM genes (XMGs), such as those encoding cytochrome P450s (CYPs), UDP‐glucuronosyltransferases (UGTs), sulfotransferases (SULTs), N‐acetyltransferases, and glutathione S‐transferases (GSTs), can alter enzyme activity, thereby affecting detoxification, hormone metabolism, and clinical outcomes. Previous research has shown the effects of genetic variants on XM in OC, underscoring the importance of pharmacogenomics in tailoring personalized treatments. However, challenges persist, including individual variability, study inconsistencies, and insufficient ovarian‐specific data on XM. This review provides a comprehensive overview of XM in OC. It emphasizes the importance of phase I and II enzymes in detoxification and biotransformation, and ABC transporters in drug metabolism and chemoresistance. This review provides insights into the emerging roles of CYPs, GSTs, glutathione peroxidases, myeloperoxidase, catalase, superoxide dismutase, SULTs, and UGTs, and addresses the need for further research to understand their influence on OC risk and prognosis. By addressing the gaps in ovarian‐specific XM research, including their role in susceptibility and treatment response, these insights have the potential to advance targeted therapeutic strategies and overcome the challenges of chemoresistance in OC.

Qualitative and quantitative changes in mitochondrial DNA associated with cervical cancer: A comprehensive review

AbstractCervical cancer is the fourth most commonly diagnosed cancer in women and is considered a preventable disease, as vaccination and screening programs effectively reduce its incidence and mortality rates. Disease physiopathology and malignant cell transformation is a complex process, but it is widely known that high‐risk HPV (hrHPV) infection is a necessary risk factor for cancer development. Mitochondria, cell organelles with important bioenergetic and biosynthetic functions, are important for cell energy production, cell growth, and apoptosis. Mitochondrial DNA is a structure that is particularly susceptible to quantitative (mtDNA copy number variation) and qualitative (sequence variations) alterations that are associated with various types of cancer. Novel biomarkers with diagnostic and prognostic value in cervical cancer can be evaluated to provide higher specificity and complement hrHPV molecular testing, which is the most recommended method for primary screening. In accordance with this, this review aimed to assess mitochondrial alterations associated with cervical cancer in clinical cervicovaginal samples, in order to unravel their possible role as specific diagnostic and prognostic biomarkers for cervical malignancy, and also to guide the understanding of their involvement in carcinogenesis, HPV infection, and disease progression.

Mutation spectra of the BRCA1 / 2 genes in human breast and ovarian cancer and germline

Abstract Annotating genomic sequence alterations is sometimes a difficult decision, particularly in missense variants with uncertain pathogenic significance and also in those presumed as germline pathogenic variants. We here suggest that mutation spectrum may also be useful for judging them. From the public databases, 982 BRCA1 /1861 BRCA2 germline missense variants and 294 BRCA1 /420 BRCA2 somatic missense variants were obtained. We then compared their mutation spectra, i.e., the frequencies of two transition‐ and four transversion‐type mutations, in each category. Intriguingly, in BRCA1 variants, A:T to C:G transversion, which was relatively frequent in the germline, was extremely rare in somatic, particularly breast cancer, cells ( p  = .03). Conversely, A:T to T:A transversion was most infrequent in the germline, but not rare in somatic cells. Thus, BRCA1 variants with A:T to T:A transversion may be suspected as somatic, and those with A:T to C:G as being in the germline. These tendencies of mutation spectrum may also suggest the biological and chemical origins of the base alterations. On the other hand, unfortunately, variants of uncertain significance (VUS) were not distinguishable by mutation spectrum. Our findings warrant further and more detailed studies.

A comprehensive literature review and meta‐analysis of the prevalence of pan‐cancer BRCA mutations, homologous recombination repair gene mutations, and homologous recombination deficiencies

AbstractThere is significant improvement in the outcomes following treatment with PARP inhibitors among patients with certain tumors that have BRCA mutations (BRCAm), homologous recombination repair (HRR) gene mutations, or homologous recombination deficiency (HRD) positivity. We performed a literature review and meta‐analysis to evaluate the prevalence of BRCA1/2m, HRR gene mutations, and HRD positivity across multiple cancers. There were 265 publications on BRCA1/2 mutation prevalence, 189 on HRR gene mutation prevalence, and 7 on HRD positivity prevalence. The prevalences of germline BRCA1m and BRCA2m were 7.8% and 5.7% for breast cancer, 13.5% and 6.6% for ovarian cancer, 0.5% and 3.5% for prostate cancer, and 1.1% and 4.1% for pancreatic cancer, respectively. The prevalences of somatic BRCA1m and BRCA2m were 3.4% and 2.7% for breast cancer, 4.7% and 2.9% for ovarian cancer, 5.7% and 3.2% for prostate cancer, and 1.2% and 2.9% for pancreatic cancer, respectively. We identified 189 studies with over 418,649 samples across 25 tumor types that examined mutations in one or more HRR genes other than BRCA1/2. The prevalence of mutations among HRR genes remained low (less than 1%), with ATM (5.2%), CHEK2 (1.6%), and PALB2 (0.9%) exhibiting the highest prevalence. Seven studies evaluated HRD positivity in breast, ovarian, and prostate cancer patients. The prevalence of HRD positivity was 56% overall (95% CI = 48%–64%). The understanding of biomarker prevalence across tumor types and standardization of biomarker assays could have important clinical implications.